Infections by antibiotic resistant bacteria and the potential for sepsis are a major health concern. Antimicrobial peptides (AMPs) like cathelicidins (CAMP) and defensins are generating considerable interest for therapeutic use as potential bactericidals, anti-LPS drugs and modulators of inflammation, and other potential uses. However, the mechanisms governing CAMP expression are largely unknown. The central hypothesis driving the proposed research is that transcription factors (TFs) from the CCAAT/enhancer binding protein (C/EBP), ETS/PU.1, CREB/ATF and the steroid/thyroid hormone receptor families control constitutive and inducible expression of CAMP in hematopoietic and epithelial tissues. We propose an investigation directed towards achieving 3 Specific Aims: [1] Identify the TFs in myeloid and epithelial cells that regulate CAMP gene transcription;[2a] Determine extent of vitamin DS-mediated induction of CAMP in various human cell types and atopic dermatitis;[2b] Identify mechanism of synergistic activation of human CAMP gene expression by retinoids and vitamin D3;[2c] Discover novel small molecules that regulate CAMP gene expression;[3] Elucidate the biological importance and potential therapeutic benefits of vitamin D3 regulation of CAMP gene expression. Specific Aims 1 and 2 will generate a comprehensive assessment of the transcriptional regulation of the CAMP gene in the myeloid and epithelial compartments and identify additional compounds that either alone or in combination with vitamin D3 may prove therapeutically useful. Specific Aim 3 will characterize the evolutionary and biological importance of antimicrobial gene regulation by vitamin D and will use parallel in vitro and in vivo mouse models that exploit a powerful genetic approach to critically examine how vitamin D3 regulates expression of CAMP in response to microbial invasion or challenge with pathogen-derived molecules. Achievement of these specific aims will provide a comprehensive knowledge of the transcriptional regulation of the CAMP gene and demonstrate the biological importance of vitamin D3-mediated regulation of antimicrobial peptides. This knowledge will lead to the development of approaches for extrinsically manipulating endogenous CAMP expression for systemic and localized therapeutic benefit of human diseases.